Abstract A14: Hedgehog inhibition delays cancer growth in C3(1)/Tag transgenic murine mammary carcinoma model

Abstract

Abstract In 1941 Apperly hypothesized that differential sunlight exposure is the cause of the latitudinal gradient in breast cancer mortality, and subsequently the effect was postulated to be due to the tumor inhibitory properties of skin produced vitamin D3. We first tested this latitudinal hypotheses using the C3(1)/Tag transgenic murine mammary carcinoma model and found that ultraviolet radiation (UVR) significantly prolongs tumor-free and overall survival but that dietary D3 has no such effect. The mechanism of this anti-mammary carcinogenesis effect of UVR is unclear but there is evidence that D3 is a potent inhibitor of the hedgehog (HH) - signaling pathway. To test this mechanistic hypothesis we compared the effects of the small molecule Smo-acting HH pathway inhibitor (HHI) BMS-833923/XL139 with those of UVR on breast cancer development in C3(1)/Tag mice. We have found that oral administration of the pharmacologic HHI delays Tag mammary carcinogenesis with an efficacy similar to that of UVR treatment (350 mJ/cm2, 3x/week), thus, time to first palpable tumor was delayed by 9 days by UVR treatment (p=0.016) and by 14 days by HHI treatment (p=0.009), compared control mice. Overall survival was delayed by 9 days by UVR treatment (p=0.19) and by 15 days by HHI treatment (p=0.011). And, we have found that HHI, like UVR, acts at an early stage of carcinogenesis (i.e. reduction of histologic changes at age 12 weeks), and initial studies of UVR + HHI treatments suggest that HHI and UVR have overlapping effects. Taken together our results are consistent with (albeit by no means proof of) our hypothesis that inhibition of mammary carcinogenesis by UVR-produced vitamin D3 underlies the latitudinal gradient and is mediated via HH inhibition. Moreover, our results suggest more broadly that HHI treatment before tumors develop may have more of an anti-cancer effect than does HHI treatment after tumors already have become clinically apparent. Note: This abstract was not presented at the conference. Citation Format: Anastasia M. Makarova, Subheksha KC, John A. Dolorito, Yefim I. Khaimskiy, Ervin H. Epstein, Jr. Hedgehog inhibition delays cancer growth in C3(1)/Tag transgenic murine mammary carcinoma model. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A14.